Neurons in the mammalian CNS (central nervous system) are highly sensitive to the availability of oxygen. It is well known that a transient critical reduction of oxygen within the intact brain, triggers a various pathological phenomena, finally a fatal brain damage [K. Nieber, Pharmacol. Ther. 1999, 82, 71]. Oxygen can become unavailable to the brain through a loss of blood flow (ischemia) following cardiac arrest or occlusion of intracranial vessels by thrombosis and embolism, or through an insufficient oxygen concentration in the blood (hypoxia).
Ischemic cell injury may arise from complex interactions biochemical cascades, which includes disturbances in among electrophysiological, hemodynamical and energy metabolism [W. Paschen and B. Djuricic, J. Neurochem. 1995, 65, 1692] and modifications in synaptic transmission [H. J. Luhmann, Prog. Neurobiol. 1996, 48, 131]. The disturbed ion homeostasis characterized by enhanced cellular K+ efflux and Na+ and Ca2+ influx is followed by a substantial extracellular acidosis, free radical formation, cell swelling, and inhibition of protein synthesis, which are connected with excitatory amino-acid receptor, Ca-dependent or ATP-dependent K-channel, etc. As explained above, the ischemic cell damage occurred by a cascade of biochemical events, not by single event. So, several strategies are suggested for the development of neuroprotective agents and it is also suggested that the effective intervention on several key steps during ischemic cascade is necessary to be an effective therapeutic agent for brain ischemia [De Keyser et al. Trends Neurosci., 1999, 22, 535; Dirnagl et al. Trends Neurosci., 1999, 22, 391; Gladstone et al. Stroke, 2002, 33, 2123].
Even after blood flow is restored, oxygen can also enhance the biochemical reactions that generate free radicals, which can lead to a potential for “reperfusion injury” to occur. Both acute and chronic injury of tissues and organs are known to be caused by ischemia-reperfusion or by endotoxins via bacterial infection. In order to prevent the brain injury caused by ischemia-reperfusion, the brain must be protected during ischemic period to avoid additional injury and pathological progressive cellular changes have to minimize.
For that purpose, the development of several neuroprotectives such as excitatory amino acid antagonists, anti-oxidants, adenosine agonists and KATP channel openers are being pursued.
Damage or death of neurons is known to be a main cause for various neurological disorders such as stroke, head trauma, Alzheimer's disease, Parkinson's disease, infant asphyxia, glaucoma and daiabetic neuropathy, etc [G. J. Zoppo et al., Drugs 1997, 54, 9: I. Sziraki et al., Neurosci, 1998, 85, 1101].
Neurons are damaged by various factors including increases in iron concentration, reactive oxygen species, and peroxidants within neurons [M. P. Mattson et al., Methods Cell Biol. 1995, 46, 187; Y. Goodman et al., Brain Res. 1996, 706, 328].
Free radicals are generated in cells by the oxidative stress. An excess of oxygen free radicals facilitates lipid peroxidation, so that peroxidants are accumulated in neurons and it also causes the change in protein synthesis and DNA. The reactive free radicals accumulated in cells are known to be responsible for a variety of diseases [J. M. McCord, Am J. Med. 2000, 108, 652]. Including inflammatory diseases such as arthritis; atherosclerosis; cardiac infarction; and neurodegenerative disease such as dementia, allergy, cancer as well as acute and chronic injury of tissues and organs.
Therefore, therapeutic approaches to minimize the damage or death of neurons have been pursued, including the inhibition of lipid peroxidation, NO formation, and reactive oxygen species induced by endotoxins. To date, anti-oxidants are reported to ameliorate the neuronal damage and death caused by an increase of iron concentration within neurons. Much effort has been continued to develop pharmaceutical drugs which are able to prevent neuronal damage by oxidative stress (Y. Zhang et al., J. Cereb. Blood Flow Metab. 1993, 13, 378).
There are reports that KATP opening is related to the induction of anti-oxidant enzymes [S. Okubo et al., Mol. and cell Biochem., 1999, 196, 3], and to decrease the release of excitatory amino acid [J-L Moreau, G. Huber, Brain Res., 1999, 31, 65].
Diazoxide, a KATP channel opener, has been reported to reversibly oxidize flavoproteins in mitochondria, resulting in inhibition of the formation of oxygen free radicals, which may protect cell injury by oxidative stress [A. A. Starkov, Biosci, Rep. 1997, 17, 273; V. P. Skulachev, Q. Rev. Biophus. 1996, 29, 169].
Infant asphyxia (IA), triggered by transient deficiency of oxygen supply during delivery, was reported to be caused by the reduction of energy production, damage of cell membrane due to oxygen free radical, release of excitatory neurotransmitters, change of intracellular ion concentrations including calcium, zinc, etc. IA is a major worldwide problem, because if IA is severe, the chances of mortality are high (approximately ⅓ of the total infant mortality). In addition, it can produce long term sequela such as movement disorders, learning disabilities, epilepsy, dystonia, mental retardation, and spasticity [C. F. Loid et. al. Physiology and Behavior, 2000, 68, 263-269].
Antioxidant enzymes, allopurinol, Vitamine C & E, free radical scavengers, inhibitors of excitatory neurotransmitters, calcium channel blockers such as nimodipine and flunarizine, inhibitors of NO formation, hyperglycemic and hypothermic therapy may be beneficial for the protection of brain injury, but their clinical application is still limited.
Glaucoma, one of the leading causes of blindness, is defined as an optic neuropathy associated with characteristic changes in optic nerve. In humans, the optic nerve consists of 1 million axons from neurons whose perikarya reside primarily in the ganglion cell layer and, to a less extent, in the inner part of the inner nuclear layer. The excavated appearance of the optic nerve head in glaucoma is thought to be caused by the death and subsequent loss of ganglion cells and their axons [N. N. Osborne, et. al. Survey of ophthalmology, 43; suppl. 1999, S102-s128].
Neuroprotective agents in glaucoma may protect death of retinal neurons, in particular the ganglion cells, either directly or indirectly. A variety of agents such as NMDA (N-methyl-D-aspartate) receptor antagonist, â-blockers, calcium antagonists, and antioxidants can be used to protect the death of retinal neurons induced by ischemia and damage of optic nerves.
Although the pathogenesis of diabetic neuropathy has not been clearly established, two main hypotheses have been proposed for it. One is metabolic abnormalities, and the other is blood flow deficits in peripheral nerve [K. Naka et. al. Diabetes Research and Clinical Practice, 1995, 30, 153-162]. Acetyl-L-carnitine (ALC) by stimulating metabolism of lipid and improving impaired nociceptive responses of neurons, and Prosaptide by releasing neutrophic factors are in clinical trials. In addition, Memantine, showing good effects on vascular dementia through the regulation of NMDA receptor, is pursuing clinical trial. Then, neuroprotective agents having a variety of mechanisms of action may be developed to treat diabetic neuropathy.
Ischemic heart diseases are usually caused by myocardial ischemia, when the oxygen supply is significantly decreased compared to the oxygen demand due to the imbalance between them [G. J. Grover, Can. J. Physiol., 1997, 75, 309; G. D. Lopaschuk et al. Science &Medicine, 1997, 42]. Myocardial ischemia triggers various pathophysiological changes progressively that will ultimately lead to irreversible myocardial injury, cell death and tissue necrosis. At a stage where the injury to the cells is reversible, this process can be prevented by early reperfusion of the myocardium. However, there is potential for “reperfusion-injury” to occur [D. J. Hearse, Medicographia, 1996, 18, 22].
To delay the ischemic cascade and to minimize the reperfusion-injury, the use of adenosine agonists, inhibitors of Na+-K+ antiport, oxygen free radical scavengers and KATP (ATP sensitive potassium channel) openers are investigated as well as ACE (Angiotensin converting enzyme) inhibitors and calcium antagonists. In addition, global ischemia occurs during cardiac surgery or during heart storage prior to transplantation. Recent studies reported that the addition of KATP openers to a hyperkalemic cardioplegic solution, improved the recovery of postischemic contractile function after normothermic or short periods of hypothermic ischemia [D. J. Chambers, D. J. Hearse, Ann. Thoar. Surg., 1999, 68, 1960.]. The use of those compounds as protectants or curatives for the organs related to “ischemia-reperfusion injury” such as retina and skeletal muscles besides heart and brain, in being investigated.
As mentioned above, since ischemic cascades proceed by complex interactions, it may be a useful strategy to develop the compound acting at more than one target site in ischemic cascade.
KATP is found in a variety of tissues including cardiac muscle, smooth muscle skeletal muscle, kidney, pancreatic β-cells, the brain and central nerve system, which makes it attractive as a drug target. However, the same diversity poses a difficulty of finding tissue selective agents.
Differently from conventional potassium channel openers, the benzopyranyl cyanoguanidine compound (BMS-180448) represented by the following formula 4 and benzopyranyl imidazole compound (BMS-191095) represented by the following formula 5, have been reported to show modest antiischemic potency with excellent cardiac selectivity. Although the compound represented by formula 5 had all desirable features to serve as a lead compound, it still retains some degree of vasorelaxant and hypotensive activities [K. S. Atwal et al., J. Med. Chem., 1995, 38, 3236; K. S. Atwal et al., J. Med. Chem., 1996, 40, 24; K. S. Atwal et al., Current Pharmaceutical Design, 1996, 2, 585]. Therefore, more cardioselective compounds which have cardioprotective potency without lowering of blood pressure significantly, still give the prospects for the development of a novel cardioprotectant.

The ratio of cancer in human diseases is being gradually increased. Angiogenesis, formation of new blood vessels, is recognized as the core process for growth and metastasis of solid tumors (Folkma, J. et al., J. Biol. Chem. 1992, 267, 10931-10934). Angiogenesis is controlled by inducers and inhibitors of angiogenesis. When the balance between them is broken, that is, when angiogenesis inducers prevail over angiogenesis inhibitors, a large quantity of new blood vessels are formed. Angiogenesis is closely related to various physiological phenomena, such as embryonic development, wound healing, chronic inflammation, hemangiomas, diabetic retinopathy, rheumatoid arthritis, psoriasis, AIDS complications, and the growth and metastasis of malignant tumors (Forkman, J., Klagsbrun. M. Science, 1987, 235, 442-447). Angiogenesis includes a series of processes such as the migration, proliferation and differentiation of endothelial cells, and is an important prerequisite for the growth and metastasis of cancers. In detail, because the growing tumor cells require the formation of blood vessels from host cells, angiogenesis promoters derived from tumors stimulate to induce the angiogenesis into the tumor mass. Afterwards, the blood vessels formed around the malignant tumors facilitate to metastasize the tumor cells to other sites. Therefore, the inhibition of angiogenesis leads to the prevention of the growth and metastasis of cancers. As one of the important research areas for the developing of anti-cancer drugs, extensive attention is paid to the finding of angiogenesis inducers and angiogenesis inhibitors, and the revealing of their working mechanisms.
Thus far, proteins such as prostamine and tumor necrotic factors, factors derived from cartilage tissues, and cortisone called angiostatic steroids and various steroid derivatives, have been found to be able to play roles as angiogenesis inhibitors. In particular, hydrocortisone exhibits anti-angiogenetic activity by cotreatment with heparin (Lee, A. et al., Science, 1983, 221, 1185-1187); Crum, R. et al., Science, 1985, 230, 1375-1378). However, these compounds have a potential problem to treat cancers effectively owing to their cytotoxicity.